Severe Herpesvirus Infections in an Adolescent without Natural Killer Cells

Biron, Christine A.; Byron, Kevin; Sullivan, John L.

doi:10.1056/nejm198906293202605

Cited by 1,152 publications

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“…Natural killer (NK) cells have the ability to immediately kill infected or transformed cells and are important for the control of acute viral infections [1,2]. By modulating dendritic cell functions, NK cells also play an important role in the development of protective T cell responses against intracellular pathogens and tumors [3,4].…”

Section: Introductionmentioning

confidence: 99%

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

2006

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Natural killer (NK) cell activity can be stimulated by different surface receptors. 2B4 is a member of the signaling lymphocyte activation molecule (SLAM)-related receptor family and is important for stimulating human NK cell cytotoxicity and cytokine production. Here we show that stimulation of human NK cells by antibody-mediated 2B4 cross-linking or incubation with target cells expressing the 2B4 ligand CD48 results in a strong down-modulation of 2B4 surface expression. This down-modulation is observed in NK cell lines, purified human NK cells and NK cell clones, and is accompanied by an internalization of 2B4. The modulation of 2B4 is dependent on the activity of Src-family kinases, but independent of PI3 K activity or actin polymerization. Inhibitory receptors can interfere with 2B4-mediated signals and NK cell activation. However, co-engagement of inhibitory killer cell Ig-like receptors has no influence on the down-modulation of 2B4. This suggests that the modulation of 2B4 expression is independent of inhibitory receptors. The lower surface expression of 2B4 after ligandinduced down-modulation results in reduced 2B4-mediated NK cell activation and cytotoxicity. The modulation of activating surface receptors may therefore be another mechanism for the fine-tuning of NK cell activity and may lead to the adaptation of NK cell cytotoxicity in tissues with high ligand expression. IntroductionNatural killer (NK) cells have the ability to immediately kill infected or transformed cells and are important for the control of acute viral infections [1,2]. By modulating dendritic cell functions, NK cells also play an important role in the development of protective T cell responses against intracellular pathogens and tumors [3,4]. The activity of NK cells is regulated by a balance of positive and negative signals, mediated by different surface receptors [5,6]. Human NK cell inhibitory receptors include members of the killer cell Ig-like receptors (KIR), and the CD94/NKG2A heterodimer, which recognize MHC class I molecules on target cells [7]. NK cell activation can be mediated by a variety of different receptors, which include the natural cytotoxicity receptors (NCR) NKp30, NKp44, NKp46, the activating receptors NKG2D and DNAM-1, and members of the signaling lymphocyte activation molecule (SLAM)-related receptors (SRR) 2B4 (CD244), NTB-A and CRACC (CS1, CD319) [6,8,9].Under physiological conditions the positive and negative signals are balanced, ensuring that NK cells do not attack normal cells [10]. Loss of MHC class I expression on infected or transformed cells can reduce the negative signal mediated by inhibitory NK cell receptors, thereby tilting the balance toward activation, resulting in NK cell-mediated lysis. Alternatively, upregulation of ligands for the activating NKG2D receptor can enhance the positive signal, resulting in the lysis of target cells with normal MHC class I expression [11]. The activity of NK cells is not only dictated by the expression of stimulating or inhibiting ligands on target cells. The ...

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Section: Introductionmentioning

confidence: 99%

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

2006

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“…In fact, the large granular CD3 À CD56 1 lymphocytes with ''natural'' cytotoxicity that express low levels of CD56 (CD56 dim ) and high levels of the Fcg-receptor type III (CD16) [1][2][3][4] represent only a minority of all of the CD3 À CD56 1 lymphocytes in the body [5,6]. CD56 dim that provide first-line defense against viruses [7,8] …”

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CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

et al. 2010

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We studied early NK-cell recovery in 29 allografted patients undergoing different lymphoreductive regimens. Already at 2 wk after graft take, the number of NK cells had reached (supra)normal levels but NK-cell subsets were skewed. The number of CD56 dim CD16 bright NK cells was low and correlated strongly with the level of hematopoiesis, whereas the number of the more abundant NK cells expressing high levels of CD56 did not. Post-transplant CD56 bright NK cells (ptCD56 bright ) differed from CD56 bright NK cells in normal controls (CD56 bright ) in being HLA-DR-and perforin-positive, CCR7 À , CD27 À , CD127 À and mostly c-kit À . CD56 bright from normal controls stimulated by IL-15 in vitro (NK ) acquired all the characteristics distinguishing CD56 bright from ptCD56 bright . IL-2 exerted similar effects. Moreover, when cultured without cytokines, ptCD56 bright , CD56 bright and NK responded similarly by upregulating CD127 and c-kit but not CCR7. IL-12 stimulated IFN-c production in ptCD56 bright , whereas CD56 bright responded only to IL-12 plus IL-15. Hence, ptCD56 bright have all the features of cytokine-stimulated CD56 bright . Because only patients with low numbers of T cells had high numbers of ptCD56 bright , we conclude that ptCD56 bright are activated CD56 bright that expand while competing with T cells for the elevated post-transplant level of IL-15.Key words: HSC transplantation . Human . Natural killer cells IntroductionIn humans, most lymphocytes without rearranged antigenreceptors express CD56 and are referred to as NK cells. Accordingly, they can be identified on the basis of a CD3 À CD56 1 phenotype [1][2][3], which excludes the subpopulation of T cells that coexpress CD56. However, this long-established definition of NK cells may be inadequate because CD3 À CD56 1 lymphocytes are heterogeneous and capable of exerting various effector functions other than killing cells with altered expression of self-MHC. Furthermore, many CD3 À CD56 1 lymphocytes do not lyse NK-cell targets when tested ex vivo and only acquire lytic activity after in vitro stimulation with cytokines. In fact, the large granular CD3 À CD56 1 lymphocytes with ''natural'' cytotoxicity that express low levels of CD56 (CD56 dim ) and high levels of the Fcg-receptor type III (CD16) [1][2][3][4] represent only a minority of all of the CD3 À CD56 1 lymphocytes in the body [5,6]. CD56 dim that provide first-line defense against viruses [7,8] 3246less abundant population of NK cells in peripheral blood expresses much higher levels of CD56 (CD56 bright ), the receptor for IL-7 (CD127), the receptor for SCF c-kit, the lymph nodehoming receptor CCR7, and displays only little cytolytic activity [3][4][5][9][10][11][12]. Approximately, half of the CD56 bright in peripheral blood express CD27, a marker virtually absent from CD56 dim [13][14][15]. Hence, CD56 bright in peripheral blood are identical or closely related to the NK cells residing in secondary lymphoid organs (SLO) that produce cytokines to guide the adaptive immune response [4-6,...

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“…Chez l'homme, le rôle des cellules NK dans le contrôle des infections virales n'est pas clairement établi du fait de la rareté des déficits touchant sélectivement ces cellules. Il semble néanmoins que ces déficits rendent les individus plus sensibles aux infections à virus persistants, comme le virus de l'herpès [10][11][12]. sécrétion d'interleukines et les facteurs de transcription qui contrôlent à la fois leur développement, leur identité et leur fonction (Tableau I).…”

Section: Nomenclature Et Principaux Sous Types D'ilcunclassified

Les cellules lymphoïdes innées

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2014

Med Sci (Paris)

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Severe Herpesvirus Infections in an Adolescent without Natural Killer Cells

Cited by 1,152 publications

References 24 publications

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

Les cellules lymphoïdes innées

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Severe Herpesvirus Infections in an Adolescent without Natural Killer Cells

Cited by 1,152 publications

References 24 publications

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

Les cellules lymphoïdes innées

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CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells